Inhibitors of cellular stress overcome acute effects of ethanol on hippocampal plasticity and learning.
Journal
Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
23
12
2019
revised:
03
04
2020
accepted:
20
04
2020
pubmed:
26
4
2020
medline:
15
7
2021
entrez:
26
4
2020
Statut:
ppublish
Résumé
Ethanol intoxication can produce marked changes in cognitive function including states in which the ability to learn and remember new information is completely disrupted. These defects likely reflect changes in the synaptic plasticity thought to underlie memory formation. We have studied mechanisms contributing to the adverse effects of ethanol on hippocampal long-term potentiation (LTP) and provided evidence that ethanol-mediated LTP inhibition involves a form of metaplasticity resulting from local metabolism of ethanol to acetaldehyde and untimely activation of N-methyl-d-aspartate receptors (NMDARs), both of which are neuronal stressors. In the present studies, we sought to understand the role of cellular stress in LTP defects, and demonstrate that ethanol's effects on LTP in the CA1 hippocampal region are overcome by agents that inhibit cellular stress responses, including ISRIB, a specific inhibitor of integrated stress responses, and GW3965, an agonist that acts at liver X receptors (LXRs) and dampens cellular stress. The agents that alter LTP inhibition also prevent the adverse effects of acute ethanol on one trial inhibitory avoidance learning. Unexpectedly, we found that the LXR agonist but not ISRIB overcomes effects of ethanol on synaptic responses mediated by N-methyl-d-aspartate receptors (NMDARs). These results have implications for understanding the adverse effects of ethanol and possibly for identifying novel paths to treatments that can prevent or overcome ethanol-induced cognitive dysfunction.
Identifiants
pubmed: 32334031
pii: S0969-9961(20)30150-9
doi: 10.1016/j.nbd.2020.104875
pmc: PMC7311293
mid: NIHMS1587947
pii:
doi:
Substances chimiques
2-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide
0
Acetamides
0
Cyclohexylamines
0
Ethanol
3K9958V90M
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
104875Subventions
Organisme : NIMH NIH HHS
ID : R01 MH101874
Pays : United States
Organisme : NIMH NIH HHS
ID : R21 MH114866
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
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